The development of FACS staining approaches utilizing tetrameric complexes  of MHC class I glycoprotein + peptide (tetramers) has greatly facilitated the analysis of both the effector and memory phases of virus-specific CD8+ T cell responses [20, 40]. This technology has moved more slowly for the CD4+ T cell subset [5, 6, 58], partly because the comparable MHC class II + peptide reagents are more difficult to produce , and partly because CD4+ T cell responses can tend to be both more diverse and smaller in magnitude.
The most useful techniques for analysing CD4+ T cell memory depend on the measurement of IFN-y production by peptide-stimulated lymphocytes, measured either in a flow cytometric assay or by ELISpot analysis after 24-48 hours of in vitro culture . Persistent CD4+ T cell memory is, for example, found for adenoviruses in healthy humans . Lack of progression to AIDS has been correlated with the continued presence of more HIV-specific IFN-y than IL-10-producing CD4+T cells in the peripheral circulation . Priming CD4+ T cell memory to a prominent Sendai virus epitope led to a more rapid antibody response and enhanced virus clearance . Low-level yHV68 persistence induced continuing CD4+ and CD8+ T cell responses that substantially prevented the establishment of further lytic, but not latent, infection following respiratory challenge of antibody-negative, |xMT mice with the same virus . Immune CD4+ and CD8+ T cells contributed to this protective effect in an additive way. Though adoptively-transferred CD4+ and CD8+ T cells promoted the recovery of |xMT mice from influenza virus infection, the CD8+ set was clearly more effective in this regard . In general, we understand less about CD4+ than CD8+ T cell memory.
Persistent CD8+ T cell memory can be demonstrated in both mice and humans following a single exposure to an inducing virus [38, 56, 61, 65, 78]. These long-lived T cells and their progeny express high levels of telomerase activity  though, under conditions of continuing antigen stimulation, telomere length may be shortened to the extent that clonal survival is impaired [102, 125]. The maintenance of CD8+ T cell memory reflects the survival of clontotypes expanded during the initial, antigen driven phase of the host response , but does not seem to require either the persistence of the inducing epitope or even the continued presence of MHC class I glycoprotein [59, 85]. What does seem to be important is exposure to the cytokines IL-7 and IL-15, both during the acute response phase and in the long term. [17, 64, 107, 119, 135].
The recall of CD8+ T cell memory can certainly provide a measure of protection against virus challenge , a possibility that is particularly attractive for viruses that vary their surface glycoproteins as a consequence of antibody-mediated selection pressure. Virus-specific CD8+ T cell responses tend to be directed at peptides derived from conserved, internal proteins [12,130], a situation that may be quite different from that found with CD4+ T cell responses . This cross-reactivity is, for instance, a good reason for thinking about the use of live influenza vaccines, combined with other mechanisms for boosting CTL memory [29, 43].
The problem with relying on the recall of CD8+ T cell memory for protection is that, though the injection of peptide-pulsed cells is generally associated with rapid elimination , the recall of effective CD8+ T cell memory to a distal site of virus growth is substantially delayed [35, 47]. When memory T cell numbers are at what might be thought of as physiological levels, there is a clear necessity for further proliferation in the lymphoid tissue, followed by emigration into the blood and localization to the target organ . Even when memory T cell numbers are very high in, for example, the lung, a rapidly growing influenza A virus will still become fully established before CD8+ T cell effectors operate to eliminate the infected cells and control the growth of the pathogen .
Thus, though vaccines directed at promoting CD8+ T cell memory can limit the damage done by lytic viruses that do not have a capacity for persistence, they seem unable to prevent the establishment of persistent infections [4, 118]. This has been clearly demonstrated for monkeys primed with candidate HIV vaccines [3, 10]. The T cells function for a time to limit the extent of virus replication, but escape variants eventually emerge .
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